Fulvestrant with or without Palbociclib and Avelumab in Treating Patients with Hormone Receptor Positive, HER2 Negative Metastatic or Recurrent Breast Cancer That Cannot Be Removed by Surgery Previously Treated with CDK and Endocrine Therapy

Trial Status: Active

This randomized pilot phase II trial studies how well fulvestrant with or without palbociclib and avelumab works in treating patients with hormone receptor positive, HER2 negative breast cancer that has spread to other parts of the body or that has come back after a period of improvement and cannot be removed by surgery, and have been previously treated with CDK and endocrine therapy. Endocrine therapy with fulvestrant prevents growth of hormone receptor positive breast cancer by blocking stimulation of tumor cells by estrogen. Palbociclib is a drug that may stop tumor cells from growing by blocking activity of two closely related enzymes (proteins that help chemical reactions in the body occur), called cyclin dependent kinases 4 and 6 (CDK 4 / 6) which are known to promote tumor cell growth. Monoclonal antibodies, such as avelumab, may help the immune system in detecting and fighting tumor cells. Giving fulvestrant with or without palbociclib and avelumab may work better in treating patients with breast cancer.

Inclusion Criteria

Participants must have histologically confirmed hormone receptor positive (HR+) HER2 negative metastatic or locally recurrent unresectable invasive breast cancer; both measurable and non-measurable disease are allowed; ER, progesterone receptor (PR) and HER2 measurements should be performed according to institutional guidelines, in a Clinical Laboratory Improvement Act (CLIA)-approved setting; cut-off values for positive/negative staining should be in accordance with current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines

Participants must have radiological or objective evidence of progression on an endocrine and CDK 4/6 inhibitor regimen in the metastatic setting, and/or relapse/progression during or within 12 months of completion of an endocrine and CDK4/6 inhibitor regimen in the adjuvant setting
* Participants must have previously been exposed to CDK4/6 inhibitor therapy in combination with endocrine therapy; exposure to any prior CDK4/6 inhibitor, (including palbociclib, abemaciclib, and ribociclib) is allowed; patients may have a line of endocrine therapy after combination endocrine and CDK4/6 inhibitor exposure
* Participants must have remained on prior endocrine and CDK4/6 therapy in the metastatic setting without progression for at least 6 months prior to study entry
* It is not mandatory to have a CDK 4/6 inhibitor containing regimen as the most recent treatment
* Participants may have had no more than 1 prior line of endocrine and CDK4/6 inhibitor therapy in the metastatic setting

Participants may have 0-1 prior lines of cytotoxic chemotherapy in the metastatic setting

Prior endocrine therapy in the metastatic setting may include any aromatase inhibitor (AI) or tamoxifen, but may not include prior fulvestrant; in the metastatic setting, 1-2 prior lines of endocrine therapy are allowed

Participants may have received radiotherapy for palliative purpose, but must not be experiencing > grade 1 treatment related toxicities, and must have completed treatment > 14 days prior to registration

Women of childbearing age, women who are made postmenopausal through use of GNRH agonists, and men must agree to use adequate contraception for the duration of protocol treatment and for at least 90 days after the last dose of palbociclib if the risk of contraception exists; adequate contraception is defined as one highly effective non-hormonal form of contraception or two effective forms of non-hormonal contraception by the participant and/or partner
* Highly effective non-hormonal contraception
** Methods of birth control which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly are considered highly-effective forms of contraception
** The following non-hormonal methods of contraception are acceptable:
*** True abstinence when this is in line with the preferred and usual lifestyle of the participant; (periodic abstinence [e.g., calendar, ovulation, symptothermal post-ovulation methods] and withdrawal are not acceptable methods of contraception)
*** Male sterilization (with appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); for female participants, the vasectomized male partner should be the sole partner OR
* Effective non-hormonal contraception
** Alternatively two of the following effective forms of contraception may be used instead:
*** Placement of non-hormonal intrauterine device (IUD) or intrauterine system (IUS); consideration should be given to the type of device being used, as there is higher failure rates quoted for certain types, e.g., steel or copper wire
*** Condom with spermicidal foam/gel/film/cream/suppository
*** Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository
*** The use of barrier contraceptives should always be supplemented with the use of spermicide; the following should be noted:
**** Failure rates indicate that, when used alone, the diaphragm and condom are not highly effective forms of contraception; therefore, the use of additional spermicides does confer additional theoretical contraceptive protection
**** However, spermicides alone are ineffective at preventing pregnancy when the whole ejaculate is spilled; therefore, spermicides are not a barrier method of contraception and should not be used alone
* It should be noted that two forms of effective contraception are required; a double barrier method is acceptable, which is defined as condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository

Premenopausal women must have a negative serum or urine pregnancy test; pregnancy testing does not need to be pursued in female participants who are:
* Age > 60 years; or
* Age < 60 with intact uterus and amenorrhea for 12 consecutive months or more AND estrogen (estradiol) levels within postmenopausal range; or
* Status-post bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation

Participant must be able to swallow and retain oral medication

Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

Participants who have had endocrine, chemotherapy, and/or biologic therapy < 14 days prior to entering the study or those who have not recovered from any prior treatment-related toxicities (must recover to no more than grade 1; alopecia, sensory neuropathy grade =< 2, or other grade =< 2 toxicity not constituting a safety risk based on investigator’s judgment are acceptable)

Participants who are receiving concurrent therapy with other investigational agents

Rapidly progressive, symptomatic, visceral spread of disease placing participant at risk of life-threatening complications in the short term

Participants with active brain metastases; stable treated brain metastases are allowed (this includes participants who have documented radiologic stability at least 4 weeks after radiotherapy, and do not require systemic steroids for management of symptoms from central nervous system [CNS] metastatic lesions)

Participants who have discontinued prior palbociclib for toxicity, or have needed more than two dose reductions for toxicity from prior palbociclib therapy; if a participant previously required dose reductions during prior palbociclib therapy and tolerated it well, for example prior dosing at 100 mg or 75 mg qd 3 weeks on 1 week off schedule, than that dose may be selected for this trial

History of allergic reactions to palbociclib or attributed to compounds of similar chemical or biologic composition to palbociclib

Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v]4.03 grade >= 3)

Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A isoenzymes are ineligible; because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list ; medical reference texts such as the Physicians’ Desk Reference may also provide this information; as part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product

Pregnant women are excluded from this study because effect of palbociclib and avelumab on a developing fetus is unknown; breastfeeding should be discontinued prior to entry onto the study

Individuals with a history of a different malignancy are ineligible except for the following circumstances; individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy; individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: ductal carcinoma in situ of the breast, cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin

II. To assess the PFS and ORR with addition of palbociclib after progression on fulvestrant alone in patients with advanced ER+/HER2- breast cancer that has progressed despite prior CDK4/6 inhibition and endocrine therapy using traditional RECIST criteria.

I. To determine the frequency and distribution of Rb loss or loss of function mutation, ESR mutations, and PI3 kinase mutations in tumors with demonstrated resistance to prior CDK4/6 inhibitor and endocrine therapy, as well as response to therapy by arm.

II. To evaluate cyclin E levels in patients who had exposure to a chemotherapy regimen between initial exposure to CDK4/6 inhibitor and entry on this study, versus those who did not receive intervening chemotherapy.

ARM A: Patients receive fulvestrant intramuscularly (IM) on days 1 and 15 of course 1 and on day 1 of courses thereafter. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with confirmed disease progression may receive palbociclib as in Arm B.

ARM B: Patients receive fulvestrant as in Arm A. Patients also receive palbociclib orally (PO) once daily (QD) on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM C: Patients receive fulvestrant and palbociclib as in Arm B. Patients also receive avelumab intravenously (IV) over 1 hour once every 14 days. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients in Arms A and B are followed up at 30 days and patients in Arm C are followed up at 90 days. Patients in all arms are then followed up every 12 weeks or 6 months thereafter.